l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans
Open accessAbstract
BACKGROUND: l-Carnitine, an abundant nutrient in red meat, accelerates atherosclerosis in mice via gut microbiota-dependent formation of trimethylamine (TMA) and trimethylamine N-oxide (TMAO) via a multistep pathway involving an atherogenic intermediate, γ-butyrobetaine (γBB). The contribution of γBB in gut microbiota-dependent l-carnitine metabolism in humans is unknown. METHODS: Omnivores and vegans/vegetarians ingested deuterium-labeled l-carnitine (d3-l-carnitine) or γBB (d9-γBB), and both plasma metabolites and fecal polymicrobial transformations were examined at baseline, following oral antibiotics, or following chronic (≥2 months) l-carnitine supplementation. Human fecal commensals capable of performing each step of the l-carnitine→γBB→TMA transformation were identified. RESULTS: Studies with oral d3-l-carnitine or d9-γBB before versus after antibiotic exposure revealed gut microbiota contribution to the initial 2 steps in a metaorganismal l-carnitine→γBB→TMA→TMAO pathway in subjects. Moreover, a striking increase in d3-TMAO generation was observed in omnivores over vegans/vegetarians (>20-fold; P = 0.001) following oral d3-l-carnitine ingestion, whereas fasting endogenous plasma l-carnitine and γBB levels were similar in vegans/vegetarians (n = 32) versus omnivores (n = 40). Fecal metabolic transformation studies, and oral isotope tracer studies before versus after chronic l-carnitine supplementation, revealed that omnivores and vegans/vegetarians alike rapidly converted carnitine to γBB, whereas the second gut microbial transformation, γBB→TMA, was diet inducible (l-carnitine, omnivorous). Extensive anaerobic subculturing of human feces identified no single commensal capable of l-carnitine→TMA transformation, multiple community members that converted l-carnitine to γBB, and only 1 Clostridiales bacterium, Emergencia timonensis, that converted γBB to TMA. In coculture, E. timonensis promoted the complete l-carnitine→TMA transformation. CONCLUSION: In humans, dietary l-carnitine is converted into the atherosclerosis- and thrombosis-promoting metabolite TMAO via 2 sequential gut microbiota-dependent transformations: (a) initial rapid generation of the atherogenic intermediate γBB, followed by (b) transformation into TMA via low-abundance microbiota in omnivores, and to a markedly lower extent, in vegans/vegetarians. Gut microbiota γBB→TMA/TMAO transformation is induced by omnivorous dietary patterns and chronic l-carnitine exposure. TRIAL REGISTRATION: ClinicalTrials.gov NCT01731236. FUNDING: NIH and Office of Dietary Supplements grants HL103866, HL126827, and DK106000, and the Leducq Foundation.
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Prior research suggests that vegans have lower TMAO levels than meat or fish eaters because of the TMAO precursors choline and carnitine in animal products.
“Prior research42,43 has suggested that vegans have lower TMAO levels than meat or fish eaters because of the TMAO precursors choline and carnitine in animal products.”
From Cardiometabolic Effects of Omnivorous vs Vegan Diets in Identical Twins: A Randomized Clinical Trial (2023) · cites this paper as [42]
The results section reports that vegans/vegetarians produced much less TMAO than omnivores after an oral l-carnitine challenge, and the Discussion links dietary l-carnitine exposure to TMAO production. The cited passages do not establish that vegans generally have lower circulating TMAO levels than meat or fish eaters, or that both choline and carnitine in animal products explain such a difference. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIn recent clinical challenge studies, TMA and TMAO generation from oral carnitine was substantially reduced in vegans/vegetarians.
“Interestingly, in small cross-sectional observational studies, plasma levels of TMAO were modestly increased in omnivores relative to vegans/vegetarians, and in recent clinical challenge studies, TMA and TMAO generation from oral carnitine was observed to be substantially reduced in vegans/vegetarians.3,19”
From Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women (2019) · cites this paper as [19]
Some TMA-containing compounds can participate in TMA/TMAO formation in a gut microbiota-dependent manner and can be generated by gut microbiota metabolism of L-carnitine.
“Some of these TMA containing compounds can participate in TMA/TMAO formation in a gut microbiota-dependent manner, and also be generated by gut microbiota metabolism of L-carnitine.1,3,16,19”
From Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women (2019) · cites this paper as [19]
Potential nutrient precursors for TMA production include c-butyrobetaine, crotonobetaine, and betaine.
“Beyond choline and carnitine, potential nutrient precursors for TMA production have been reported, including the carnitine related metabolites c-butyrobetaine and crotonobetaine, and the choline oxidation product betaine.1,16,19”
From Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women (2019) · cites this paper as [19]
In small cross-sectional observational studies, plasma TMAO levels were modestly increased in omnivores relative to vegans/vegetarians.
“Interestingly, in small cross-sectional observational studies, plasma levels of TMAO were modestly increased in omnivores relative to vegans/vegetarians, and in recent clinical challenge studies, TMA and TMAO generation from oral carnitine was observed to be substantially reduced in vegans/vegetarians.3,19”
From Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women (2019) · cites this paper as [19]
Gut microbiota-derived metabolite TMAO has been linked to atherosclerotic heart disease in both mice and humans.
“The gut microbiota-derived metabolite TMAO has been linked to atherosclerotic heart disease in both mice and humans.185”
From Interaction between microbiota and immunity in health and disease (2020) · cites this paper as [185]
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- l-carnitine). Cultures were grown under anaerobic conditions at 37°C for 12 days, diluting 1:100 in enrichment media every 2 days. After 12 days in culture, enriched communities were spread and plated in BHI plates supplemented with 500 μM l-carnitine. To reduce the complexity of the microbial community, single colonies, groups of 2-3 colonies, and groups of 4+ colonies totaling 768 cultures were then picked and inoculated into 1 ml of BHI containing 50 μM d 9 -l-carni- tine. After 24 hours at 37°C under anaerobic conditions, a sample of culture supernatant was collected and quenched by addition of formic acid to a final concentration of 0.1%. The amount of d 9 -TMA produced was determined by LC-MS/MS. The top d 9 -TMA-producing well was selected and replated, repeating the community simplification steps as described above. Once the top d 9 -TMA-producing community was identified, the cells were spread and plated. Single colonies were iso- lated and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) using a Biotyp- er System (Bruker Daltonics Inc.) (64). Isolates with similar high- confidence identification were pooled into 4 separate species pools, SP1 through SP4. All isolates with no reliable identification by MS were pooled into a fifth pool, SP5, and subsequently identified by 16S-rRNA sequence analysis (AccuGENX-ID, Accugenix). Single microbial isolates or pools of isolates were evaluated alone or in combination for their ability to catabolize compounds of the l-carnitine pathway. Starter cultures were grown in BHI for 24 hours at 37°C under anaerobic conditions. Cells were harvested by centrifu- gation and washed in M9 minimal medium. After washing, cells were resuspended in M9 supplemented with 50 μM d 9 -l-carnitine or 50 μM d 9 -γBB as indicated. For kinetic experiments with fecal communities, fecal slurries prepared as described above were used instead of starter cultures. Reactions were allowed to proceed for up to 32 hours at 37°C under anaerobic conditions, as indicated. Samples of culture super- natant quenched by addition of formic acid to a final concentration of 0.1% were analyzed by LC-MS/MS to quantify concentrations of d 9 -TMA, d 9 -l-carnitine, and/or d 9 -γBB. Human fecal polymicrobial incubation with deuterium-labeled l-car- nitine and γBB. Human fecal samples were collected, snap-frozen in glycerol stock using liquid nitrogen, and maintained at -80°C until use. Feces (50 mg) was incubated with 1 ml reaction solution contain- ing 150 mM d 3 -l-carnitine, d 9 -l-carnitine, or d 9 -γBB as indicated with- in 10 mM HEPES, pH 7.4, in a gas-tight reaction vial under anaerobic (Argon) conditions at 37°C. Reactions were stopped 16 hours later by addition of formic acid to a final concentration of 0.1%. The products were determined by LC-MS/MS with d 4 -choline and 13 C 3 , 15 N-TMA added as internal standards and normalized to mass of fecal content. General statistics. A Mann-Whitney (Wilcoxon rank sum test) 2-tailed nonparametric test or a Pearson χ 2 test was used to compare group means and AUCs. A Wilcoxon matched-pairs test or a zero- inflated linear mixed-effects model was used to assess linked human and baseline treatment effects as deemed appropriate. A repeated- measures 1-way ANOVA test was used to assess differences of base- line plasma concentrations of γBB and TMAO between multiple visits. For all analyses a P value less than 0.05 was considered significant. All
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- Authors
- Koeth, R. A., Lam-Galvez, B. R., Kirsop, J., Wang, Z., Levison, B. S., Gu, X., Copeland, M. F., Bartlett, D., Cody, D. B., Dai, H. J., Culley, M. K., Li, X. S., Fu, X., Wu, Y., Li, L., DiDonato, J. A., Tang, W. H. W., Garcia-Garcia, J. C., & Hazen, S. L.
- Affiliations
- Cleveland Clinic (US)
- Cleveland Clinic Lerner College of Medicine (US)
- Procter & Gamble (United States) (US)
- Cleveland State University (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2018-12-10
- Volume
- 129
- Issue
- 1
- Pages
- 373-387
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC6307959
- OpenAlex
- W2903641122
- Cited by
- 327
- References
- 65
- Citations by year
- 2026: 25 · 2025: 44 · 2024: 37 · 2023: 48 · 2022: 47 · 2021: 51 · 2020: 51 · 2019: 23 · 2018: 1
- FWCI
- 11.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NIH and Office of Dietary Supplements (HL103866, HL126827, DK106000)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Polyamine Metabolism and Applications
- Keywords
- L-carnitine, trimethylamine N-oxide, trimethylamine, gamma-butyrobetaine, gut microbiota, atherosclerosis, omnivorous diet, vegan diet, Clostridiales, antibiotic exposure, plasma carnitine
- MeSH terms
- Vegans, Eubacteriales, Clostridiales, Gastrointestinal Microbiome, Animals, Betaine, Carnitine, Female, Humans, Male, Methylamines, Pilot Projects, Atherosclerosis, Mice
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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